Genetic epidemiologists often gather outcome-dependent samples of family data to measure within-family associations of genetic factors with disease outcomes. Generalized linear mixed models provide effective methods to estimate within-family associations but typically require parametric specification of the random effects distribution. Although misspecification of the random effects distribution often leads to little bias in estimated regression coefficients in standard, prospective clustered data settings, some recent studies suggest that such misspecification will impact parameter estimates from outcome-dependent cluster sampling designs. Using analytic results, simulation studies and fits to example data, this study examines the effect of misspecification of random effects distributions on parameter estimates in clustered data settings with outcome-dependent sampling. We show that the effects are consistent with results from prospective cluster sampling settings. In particular, ascertainment corrected mixed model methods that assume normally distributed random intercepts and conditional likelihood approaches provide accurate estimates of within-family covariate effects even under a misspecified random effects distribution.
Ascertainment correction; conditional likelihood; generalized linear mixed models; misspecified mixing distributions
Most longitudinal studies of depressive symptoms reported mean symptom scores that tend to obscure interindividual heterogeneity in the symptom experience. The identification of subgroups of patients with distinct trajectories of depressive symptoms may help identify high risk individuals who require an intervention. This study aimed to identify subgroups of breast cancer patients (n=398) with distinct trajectories of depressive symptoms in the first six months after surgery, as well as predictors of these trajectories.
Growth mixture modeling was used to identify the latent classes based on Center for Epidemiological Studies-Depression scale scores completed prior to and monthly for six months after surgery.
Four latent classes of patients with distinct depressive symptom trajectories were identified: Resilient (38.9%), Subsyndromal (45.2%), Delayed (11.3%), and Peak (4.5%). Patients in the Subsyndromal class were significantly younger than patients in the Resilient class. Compared to the Resilient class, Subsyndromal, Delayed, and Peak classes had higher mean trait and state anxiety scores prior to surgery. Except for axillary lymph node dissection (ALND), disease- and treatment-related characteristics did not differ across the classes. A greater proportion of women in the Subsyndromal class had an ALND compared to those in the Resilient class.
Breast cancer patients experience different trajectories of depressive symptoms after surgery. Of note, over 60% of these women were classified into one of three distinct subgroups with clinically significant levels of depressive symptoms. Identification of phenotypic and genotypic predictors of symptom trajectories after cancer treatment warrants additional investigation.
breast cancer; depression; anxiety; growth mixture modeling; latent profiles; psychological distress
Purpose. 123I-metaiodobenzylguanidine (MIBG) is used for the diagnostic evaluation of neuroblastoma. We evaluated the relationship between norepinephrine transporter (NET) expression and clinical MIBG uptake. Methods. Quantitative reverse transcription PCR (N = 82) and immunohistochemistry (IHC; N = 61) were performed for neuroblastoma NET mRNA and protein expression and correlated with MIBG avidity on diagnostic scans. The correlation of NET expression with clinical features was also performed. Results. Median NET mRNA expression level for the 19 MIBG avid patients was 12.9% (range 1.6–73.7%) versus 5.9% (range 0.6–110.0%) for the 8 nonavid patients (P = 0.31). Median percent NET protein expression was 50% (range 0–100%) in MIBG avid patients compared to 10% (range 0–80%) in nonavid patients (P = 0.027). MYCN amplified tumors had lower NET protein expression compared to nonamplified tumors (10% versus 50%; P = 0.0002). Conclusions. NET protein expression in neuroblastoma correlates with MIBG avidity. MYCN amplified tumors have lower NET protein expression.
Based on the recent literature and collective experience, an international consortium developed revised guidelines for the diagnosis of behavioural variant frontotemporal dementia. The validation process retrospectively reviewed clinical records and compared the sensitivity of proposed and earlier criteria in a multi-site sample of patients with pathologically verified frontotemporal lobar degeneration. According to the revised criteria, ‘possible’ behavioural variant frontotemporal dementia requires three of six clinically discriminating features (disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/compulsive behaviours, hyperorality and dysexecutive neuropsychological profile). ‘Probable’ behavioural variant frontotemporal dementia adds functional disability and characteristic neuroimaging, while behavioural variant frontotemporal dementia ‘with definite frontotemporal lobar degeneration’ requires histopathological confirmation or a pathogenic mutation. Sixteen brain banks contributed cases meeting histopathological criteria for frontotemporal lobar degeneration and a clinical diagnosis of behavioural variant frontotemporal dementia, Alzheimer’s disease, dementia with Lewy bodies or vascular dementia at presentation. Cases with predominant primary progressive aphasia or extra-pyramidal syndromes were excluded. In these autopsy-confirmed cases, an experienced neurologist or psychiatrist ascertained clinical features necessary for making a diagnosis according to previous and proposed criteria at presentation. Of 137 cases where features were available for both proposed and previously established criteria, 118 (86%) met ‘possible’ criteria, and 104 (76%) met criteria for ‘probable’ behavioural variant frontotemporal dementia. In contrast, 72 cases (53%) met previously established criteria for the syndrome (P < 0.001 for comparison with ‘possible’ and ‘probable’ criteria). Patients who failed to meet revised criteria were significantly older and most had atypical presentations with marked memory impairment. In conclusion, the revised criteria for behavioural variant frontotemporal dementia improve diagnostic accuracy compared with previously established criteria in a sample with known frontotemporal lobar degeneration. Greater sensitivity of the proposed criteria may reflect the optimized diagnostic features, less restrictive exclusion features and a flexible structure that accommodates different initial clinical presentations. Future studies will be needed to establish the reliability and specificity of these revised diagnostic guidelines.
behavioural variant frontotemporal dementia; diagnostic criteria; frontotemporal lobar degeneration; FTD; pathology
Deficits in the generation and control of saccades have been described in clinically-defined frontotemporal dementia (FTD) and Alzheimer’s disease (AD). Because clinical FTD syndromes can correspond to a number of different underlying neuropathologic FTD and non-FTD diagnoses, we sought to determine the saccade abnormalities associated with autopsy-defined cases of FTLD and AD.
Participants and design
An infrared eye tracker was used to record visually guided saccades to ten degree targets and antisaccades in 28 autopsy-confirmed FTD and 10 AD subjects, an average of 35.6 ± 10 months prior to death and 27 age-matched normal controls (NC). 12 FTD subjects had FTLD-TDP pathology, 15 had FTLD-tau pathology and one showed FTLD-FUS pathology. Receiver operating curve (ROC) statistics were used to determine diagnostic value of oculomotor variables. Neuroanatomical correlates of oculomotor abnormalities were investigated using voxel-based morphometry (VBM).
All FTD and AD subjects were impaired relative to NC on the antisaccade task. However, only FTLD-tau and AD cases displayed reflexive visually-guided saccade abnormalities. AD cases displayed prominent increases in horizontal saccade latency that differentiated them from FTD cases. Impairments in velocity and gain were most severe in individuals with Progressive Supranuclear Palsy (PSP) but were also present in other tauopathies. Vertical and horizontal saccade velocity and gain were able to differentiate PSP cases from other patients. Vertical saccade velocity was strongly correlated with dorsal midbrain volume.
Decreased visually-guided saccade velocity and gain are suggestive of underlying tau pathology in FTD, with vertical saccade abnormalities most diagnostic of PSP.
Frontotemporal Dementia; Corticobasal Degeneration; Progressive Supranuclear Palsy; Ocular Motility
Ewing sarcoma can arise in either bone or soft tissue locations. We sought to investigate if patient characteristics, treatment strategies, and outcomes differ between skeletal Ewing sarcoma and extraskeletal Ewing sarcoma (EES).
Patients < 40 years of age with Ewing sarcoma or peripheral primitive neuroectodermal tumor (PNET) reported to the US SEER database from 1973 to 2007 were evaluated based on skeletal (n=1519) vs. extraskeletal (n=683) site of origin. Patient characteristics were compared using Fisher exact tests. Overall survival was estimated by Kaplan-Meier methods and compared using log-rank tests and Cox models.
Patients with EES had a higher mean age (19.5 vs. 16.3 years; p < 0.001) and were less likely to be male (53.4% vs. 63.3%; p < 0.001) or white (84.8% vs. 92.5%; p < 0.001) compared to patients with skeletal tumors. Extraskeletal tumors were more likely to arise in axial locations (72.9% vs. 54.2%; p = 0.001), though less likely to arise specifically in the pelvis (19.8% vs. 26.6%; p < 0.001). Metastatic status or tumor size did not differ by group. Five-year overall survival was superior for localized EES compared to localized skeletal tumors (69.7% vs. 62.6%; p = 0.02). The hazard ratio for death in patients with localized skeletal tumors compared to localized EES was 2.36 (95% CI 1.61-3.44) beyond 24 months from initial diagnosis.
Patient characteristics and outcomes differ among patients with EES compared to patients with skeletal Ewing sarcoma. These findings may have important implications for patient care.
Ewing sarcoma; extraskeletal; extraosseous; PNET; SEER
Different degenerative brain diseases result in distinct personality changes as a result of divergent patterns of brain damage, however, little is known about the natural history of these personality changes throughout the course of each disease.
To investigate how interpersonal traits change as a function of degenerative brain disease type and severity.
Using the Interpersonal Adjective Scales, informant ratings of retrospective premorbid and current scores for dominance, extraversion, warmth, and ingenuousness were collected annually for one to four years on 188 patients [67 behavioural variant frontotemporal dementia (bvFTD), 40 semantic dementia (SemD), 81 Alzheimer’s disease (AD)] and 65 older healthy controls. Using random coefficient models, interpersonal behaviour scores at very mild, mild, or moderate-to-severe disease stages were compared within and between patient groups.
Group-level changes from premorbid personality occurred as a function of disease type and severity, and were apparent even at a very mild disease stage (Clinical Dementia Rating=0.5) for all three diseases. Decreases in interpersonal traits associated with emotional affiliation (i.e., extraversion, warmth, and ingenuousness) and more rigid interpersonal behaviour differentiated bvFTD and SemD patients from AD patients.
Specific changes in affiliative interpersonal traits differentiate degenerative brain diseases even at a very mild disease stage, and patterns of personality change differ across bvFTD, SemD, and AD with advancing disease. This study describes the typical progression of change of interpersonal traits in each disease, improving the ability of clinicians and caregivers to predict and plan for symptom progression.
neurodegenerative diseases; dementia; personality; affiliation; mixed effects model
To develop a practical informant-based screening tool that reliably identifies patients with mild cognitive impairment (MCI) and dementia, we analyzed data from a sample of patients and normal controls seen in a memory clinic. All subjects were evaluated with the Clinical Dementia Rating scale (CDR). Individual CDR responses were dichotomized and entered into a forward stepwise multivariable logistic regression model. Four independent predictors of MCI and dementia thus identified were combined into a prediction rule that was validated in a separate cohort drawn from the same clinic. Using a cut point of 2 or more positive responses to the four questions, the final prediction rule had sensitivity of 95% (95% CI 92 – 97%) for MCI or dementia, and a specificity of 91% (95% CI 86 – 95%). When applied to the validation cohort, the sensitivity for MCI or dementia was 96% (95% CI 94 – 98%), and the specificity was 96% (95% CI 92 – 98%). Using both cohorts, the positive likelihood ratio for MCI or dementia was 15.6 (95% CI 14.0 – 17.3) and the negative likelihood ratio 0.05 (95% CI 0.04 – 0.07). This tool has the potential to identify patients who warrant further cognitive evaluation in busy outpatient or emergency department settings.
Dementia; Mild Cognitive Impairment; Screening; Diagnosis
To provide a focused, detailed assessment of the symptom experiences of intensive care unit patients at high risk of dying and to evaluate the relationship between delirium and patients' symptom reports.
Prospective, observational study of patients' symptoms.
Two intensive care units in a tertiary medical center in the western United States.
One hundred seventy-one intensive care unit patients at high risk of dying.
Measurements and Main Results
Patients were interviewed every other day for up to 14 days. Patients rated the presence, intensity (1 = mild; 2 = moderate; 3 = severe), and distress (1 = not very distressing; 2 = moderately distressing; 3 = very distressing) of ten symptoms (that is, pain, tired, short of breath, restless, anxious, sad, hungry, scared, thirsty, confused). The Confusion Assessment Method–Intensive Care Unit was used to ascertain the presence of delirium. A total of 405 symptom assessments were completed by 171 patients. Patients' average age was 58 ± 15 yrs; 64% were males. Patients were mechanically ventilated during 34% of the 405 assessments, and 22% died in the hospital. Symptom prevalence ranged from 75% (tired) to 27% (confused). Thirst was moderately intense, and shortness of breath, scared, confusion, and pain were moderately distressful. Delirium was found in 34.2% of the 152 patients who could be evaluated. Delirious patients were more acutely ill and received significantly higher doses of opioids. Delirious patients were significantly more likely to report feeling confused (43% vs. 22%, p = .004) and sad (46% vs. 31%, p = .04) and less likely to report being tired (57% vs. 77%, p = .006) than nondelirious patients.
Study findings suggest that unrelieved and distressing symptoms are present for the majority of intensive care unit patients, including those with delirium. Symptom assessment in high-risk intensive care unit patients may lead to more focused interventions to avoid or minimize unnecessary suffering.
critical care; pain; symptoms; symptom assessment; palliative care; delirium
Litière et al. (2007) presented the results of simulation studies that they claimed showed that misspecification of the shape of the random effects distribution can produce marked increases in Type II error (decreases in power) of tests based on fits of generalized linear mixed models. However, the paper contains a logical fallacy that invalidates this claim. We present logically correct simulation studies that demonstrate little increase in Type II error, consistent with the earlier work that shows little effect due to misspecification.
Conditional likelihood; generalized linear mixed models; misspecified random effect distributions; power
Statistical models that include random effects are commonly used to analyze longitudinal and correlated data, often with the assumption that the random effects follow a Gaussian distribution. Via theoretical and numerical calculations and simulation, we investigate the impact of misspecification of this distribution on both how well the predicted values recover the true underlying distribution and the accuracy of prediction of the realized values of the random effects. We show that, although the predicted values can vary with the assumed distribution, the prediction accuracy, as measured by mean square error, is little affected for mild to moderate violations of the assumptions. Thus, standard approaches, readily available in statistical software will often suffice. The results are illustrated using data from the Heart and Estrogen/Progestin Replacement Study using models to predict future blood pressure values.
Mean square error of prediction; mixture distribution; non-normality
To determine if socioemotional disinhibition and executive dysfunction are related to dissociable patterns of brain atrophy in neurodegenerative disease. Previous studies have indicated that behavioral and cognitive dysfunction in neurodegenerative disease are linked to atrophy in different parts of the frontal lobe, but these prior studies did not establish that these relationships were specific, which would best be demonstrated by a double dissociation.
Subjects included 157 patients with neurodegenerative disease. A semi-automated parcellation program (Freesurfer) was used to generate regional cortical volumes from structural MRI scans. Regions of interest (ROIs) included anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), middle frontal gyrus (MFG) and inferior frontal gyrus (IFG). Socioemotional disinhibition was measured using the Neuropsychiatric Inventory. Principal component analysis including three tasks of executive function (EF; verbal fluency, Stroop Interference, modified Trails) was used to generate a single factor score to represent EF.
Partial correlations between ROIs, disinhibition, and EF were computed after controlling for total intracranial volume, MMSE, diagnosis, age, and education. Brain regions significantly correlated with disinhibition (ACC, OFC, IFG, and temporal lobes) and EF (MFG) were entered into separate hierarchical regressions to determine which brain regions predicted disinhibition and EF. OFC was the only brain region to significantly predict disinhibition and MFG significantly predicted executive functioning performance. A multivariate general linear model demonstrated a significant interaction between ROIs and cognitive-behavioral functions.
These results support a specific association between orbitofrontal areas and behavioral management as compared to dorsolateral areas and EF.
Brain behaviour and relationships; prefrontal; emotion regulation; executive control
The incidence of Ewing sarcoma varies by race, with very low rates among persons of African and East Asian ancestry. The incidence by race of other mesenchymal tumors that also harbor EWSR1 translocations has not been studied.
The SEER database was queried to find cases of mesenchymal tumors associated with EWSR1 translocations: Ewing sarcoma; clear cell sarcoma; extraskeletal myxoid chondrosarcoma; myxoid liposarcoma; desmoplastic small round cell tumor and myoepithelial tumor. Age-adjusted incidence rates were calculated for white, African-American, and Asian/Native American populations and compared statistically.
Ewing sarcoma was significantly less common in the African-American and Asian/Native American populations compared to the white population, with incidence rate ratios of 0.12 (95% confidence interval 0.08 – 0.20; p < 0.001) and 0.54 (95% confidence interval 0.41 – 0.69; p < 0.001), respectively. Desmoplastic small round cell tumor was significantly more common in the African-American population compared to the white population (incidence rate ratio 3.0; 95% confidence interval 1.62 – 5.49; p < 0.001). Myxoid liposarcoma was significantly less common in the Asian/Native American population compared to the white population (incidence rate ratio 0.72; 95% confidence interval 0.56 – 0.92; p-value 0.006). The incidence rates for extraskeletal myxoid chondrosarcoma, myoepithelial tumors, and clear cell sarcoma did not differ significantly by race.
Tumors associated with EWSR1 translocation are not uniformly more common in people of European ancestry.
The relationship between race and EWSR1 somatic translocation is complex. Future studies investigating the genetic epidemiology of EWSR1 translocated tumors are required.
Mesenchymal tumors; sarcoma translocations; EWSR1; race; SEER
In standard regression analyses of clustered data, one typically assumes that the expected value of the response is independent of cluster size. However, this is often false. For example, in studies of surgical interventions, investigators have frequently found surgery volume and outcomes to be related to the skill level of the surgeons. This paper examines the effect of ignoring response-dependent, informative, cluster sizes on standard analytical methods such as mixed-effects models and conditional likelihood methods using analytic calculations, simulation studies and an example from a study of periodontal disease. We consider the case in which cluster sizes and responses share random effects which we assume to be independent of the covariates. Our focus is on maximum likelihood methods that ignore informative cluster sizes, and we show that they exhibit little bias in estimating covariate effects that are uncorrelated with the random effects associated with cluster sizes. However, estimation of covariate effects that are associated with the random effects can be biased. In particular, for models with random intercepts only, ignoring informative cluster sizes can yield biased estimators of the intercept but little bias in estimation of all covariate effects.
Conditional likelihood; Generalized linear mixed model; Misspecified mixing distribution; Random slope
Both HIV and aging impact performance on neuropsychological testing; however, evidence for differences between HIV effects in younger compared to older subjects (interaction effects) is limited and the findings have been inconsistent. Coexisting morbidities that contribute to cognitive impairment in HIV include those not directly referable to infection, per se, and are more prevalent with advancing age, increasing the likelihood that HIV and age effects may be largely independent. As individuals survive with HIV into geriatric age groups, greater clarity on these relationships is essential. We present cross-sectional data from a large (n = 450) cohort designed to analyze HIV, age, and interaction effects using a well-matched cohort of HIV negative individuals. Results reveal limited evidence for interaction effects between HIV and age on neuropsychological performance. We conclude that older age does not significantly influence neuropsychological performance among HIV patients when seronegative controls are largely composed of individuals from a similar socioeconomic background.
HIV; AIDS Dementia Complex; neuropsychological tests; aging
Rationale: Endothelin-1 (ET1) is dysregulated in pulmonary hypertension (PH). It may be important in the pathobiology of congenital diaphragmatic hernia (CDH).
Objectives: We hypothesized that ET1 levels in the first month would be higher in infants with CDH who subsequently expired or were discharged on oxygen (poor outcome). We further hypothesized that ET1 levels would be associated with concurrent severity of PH.
Methods: We sampled plasma at 24 to 48 hours, and 1, 2, and 4 weeks of age in 40 prospectively enrolled newborns with CDH. We performed echocardiograms to estimate pulmonary artery pressure at less than 48 hours of age and weekly to 4 weeks. PH was classified in relationship to systemic blood pressure (SBP): less than 2/3 SBP, 2/3 SBP-systemic is related to pressure, or systemic-to-suprasystemic pressure.
Measurements and Main Results: ET1 levels at 1 and 2 weeks were higher in infants with poor outcome compared with infants discharged on room air (median and interquartile range: 27.2 [22.6, 33.7] vs. 19.1 [16.1, 29.5] pg/ml, P = 0.03; and 24.9 [17.6, 39.5] vs. 17.4 [13.7, 21.8] pg/ml, P = 0.01 at 1 and 2 weeks, respectively). Severity of PH was significantly associated with increasing ET1 levels at 2 weeks (16.1 [13.7, 21.8], 21.0 [17.4, 31.1], and 23.6 [21.9, 39.5] pg/ml for increasing PH class, P = 0.03). Increasing severity of PH was also associated with poor outcome at that time (P = 0.001).
Conclusions: Infants with CDH and poor outcome have higher plasma ET1 levels and severity of PH than infants discharged on room air. Severity of PH is associated with ET1 levels.
bronchopulmonary dysplasia; biological markers; echocardiography
Since osteosarcoma is extremely rare in children ≤ 5 years of age, we sought to investigate if tumor characteristics, treatment strategies, and outcomes differ compared to older patients.
Patients < 20 years of age with high-grade osteosarcoma reported to national SEER database from 1973–2006 were separated into two groups based on age at diagnosis: ≤ 5 years (n=49) and 6–19 years (n = 1687). Patient, tumor, and treatment characteristics were compared using Fisher exact tests. Overall survival was estimated by Kaplan-Meier methods and compared using log-rank tests and Cox models.
Patients ≤ 5 years had higher proportions of osteosarcoma arising from the upper limb compared to older patients (24.5% vs. 11.2%; p = 0.006). These very young patients had a significantly higher proportion of telangiectatic histology (10.2% vs. 2.9%; p = 0.017). Sex, metastatic status, race, or ethnicity did not differ by age. A higher proportion of very young patients was treated with amputation (55.2% vs. 27.3%; p = 0.002). Five-year overall survival was inferior for patients with localized osteosarcoma 5 years of age or younger compared to older children (51.9% vs. 67.3%; p = 0.03). After controlling for metastatic status, year of diagnosis, and tumor site, the hazard ratio for death in very young patients was 1.6 (95% confidence interval 1.02 – 2.36; p = 0.04) compared to older patients.
Tumor characteristics, treatment, and outcomes differ among children ≤ 5 years of age compared to older pediatric patients. These differences may reflect differences in tumor biology.
osteosarcoma; young children; treatment; outcome; SEER
Ewing sarcoma (ES) is a malignant tumor of bone or soft tissue. One of the few risk factors for developing ES is race, with a higher incidence in populations of European rather than African or Asian ancestry. The goal of this study was to evaluate racial and ethnic differences in presentation and overall survival (OS) among patients diagnosed with ES before age 40.
Data from the SEER database identified1715 patients with ES <40 years of age from 1973–2005. Racial and ethnic group differences were compared using chi square tests. OS was estimated by Kaplan-Meier analysis and compared using log-rank tests and Cox models.
Black patients had significantly more soft-tissue tumors compared to white non-Hispanic patients (p < 0.0001). Asian and white Hispanic patients had an intermediate frequency of soft tissue tumors that also differed from white non-Hispanic patients (p < 0.0001). White Hispanic patients presented with a higher proportion of larger tumors compared to white non-Hispanic patients (p = 0.042). Black patients were older than white non-Hispanic patients (p = 0.012). Sex, frequency of pelvic tumors, and metastatic status did not differ by ethnicity or race. OS was different according to race and ethnicity. Even after controlling for known confounders, OS was significantly worse for black, Asian, and white Hispanic patients compared to white non-Hispanic patients (p=0.0031, p= 0.0182 and p=0.0051, respectively).
Ethnic and racial differences in characteristics and outcomes for patients with ES exist. Understanding the etiology of these differences requires further study.
Ewing sarcoma family of tumors; prognosis; soft-tissue; race; ethnicity; SEER
Cognitive deficits in semantic dementia have been attributed to anterior temporal lobe grey matter damage; however, key aspects of the syndrome could be due to altered anatomical connectivity between language pathways involving the temporal lobe. The aim of this study was to investigate the left language-related cerebral pathways in semantic dementia using diffusion tensor imaging-based tractography and to combine the findings with cortical anatomical and functional magnetic resonance imaging data obtained during a reading activation task. The left inferior longitudinal fasciculus, arcuate fasciculus and fronto-parietal superior longitudinal fasciculus were tracked in five semantic dementia patients and eight healthy controls. The left uncinate fasciculus and the genu and splenium of the corpus callosum were also obtained for comparison with previous studies. From each tract, mean diffusivity, fractional anisotropy, as well as parallel and transverse diffusivities were obtained. Diffusion tensor imaging results were related to grey and white matter atrophy volume assessed by voxel-based morphometry and functional magnetic resonance imaging activations during a reading task. Semantic dementia patients had significantly higher mean diffusivity, parallel and transverse in the inferior longitudinal fasciculus. The arcuate and uncinate fasciculi demonstrated significantly higher mean diffusivity, parallel and transverse and significantly lower fractional anisotropy. The fronto-parietal superior longitudinal fasciculus was relatively spared, with a significant difference observed for transverse diffusivity and fractional anisotropy, only. In the corpus callosum, the genu showed lower fractional anisotropy compared with controls, while no difference was found in the splenium. The left parietal cortex did not show significant volume changes on voxel-based morphometry and demonstrated normal functional magnetic resonance imaging activation in response to reading items that stress sublexical phonological processing. This study shows that semantic dementia is associated with anatomical damage to the major superior and inferior temporal white matter connections of the left hemisphere likely involved in semantic and lexical processes, with relative sparing of the fronto-parietal superior longitudinal fasciculus. Fronto-parietal regions connected by this tract were activated normally in the same patients during sublexical reading. These findings contribute to our understanding of the anatomical changes that occur in semantic dementia, and may further help to explain the dissociation between marked single-word and object knowledge deficits, but sparing of phonology and fluency in semantic dementia.
semantic dementia; semantic knowledge; diffusion tensor-based tractography; functional MRI; voxel-based morphometry
To examine efficacy and predictors of response to a lifestyle intervention for obese youth.
Retrospective chart review of 214 children and adolescents aged 8-19 years. Linear regression identified baseline predictors of response (Δ BMI z-score) at first and ultimate follow-up visits.
Mean Δ BMI z-score from baseline was -0.04 (p <0.001) at first follow-up and -0.09 (p <0.001) at ultimate follow-up (median time 10 mo) among 156 children and adolescents. Higher baseline BMI z-score predicted poor response at first and ultimate follow-up, explaining 10% of variance in response. Fasting insulin explained 6% of response variance at first follow-up. Δ BMI z-score at the first visit along with baseline BMI z-score explained up to 50% of variance in response at ultimate visit.
Clinic-based interventions improve weight status. Baseline variables predict only a small proportion of response; response at the first visit is a more meaningful tool to guide clinical decisions.
obesity; insulin; lifestyle counseling; adolescents; weight loss
A provocative finding from several double-blind clinical trials has been the association between greater adherence to placebo study medication and better health outcomes. We used data from the Studies of Left Ventricular Dysfunction (SOLVD) Treatment Trial (SOLVD-TT) and the SOLVD Prevention Trial (SOLVD-PT) to examine whether such associations could be validated and to examine several sources of bias and potential confounding.
Survival analytic methods were used to estimate the association between placebo adherence and several health outcomes, employing a number of modeling techniques to test for the existence of alternative explanations for the association. Higher adherence was defined as having taken ≥75% of prescribed study medication.
Higher placebo adherence was associated with improved overall survival in both SOLVD-TT and SOLVD-PT [hazard ratio (HR) = 0.52, 95% confidence interval (CI): 0.35 to 0.79 and HR = 0.52, 95%CI: 0.38 to 0.71, respectively]. Associations were similar for fatal or non-fatal cardiovascular or coronary heart disease events. Adjustment for both modifiable and non-modifiable cardiac risk factors (including age, gender, diabetes, blood pressure, smoking, weight, alcohol use, and levels of education) had minimal effect on the strength of the association. Little evidence of bias was found as an explanation for this relationship.
In these two trials, better adherence to placebo was associated with markedly superior health outcomes, including total in-study mortality and incident cardiovascular events. No important confounders were identified. These data suggest there may exist strong but unrecognized determinants of health outcomes for which placebo adherence is a marker.
placebo; health outcome
There are currently no FDA-approved treatments for frontotemporal lobar degeneration (FTLD). The objectives of this study were to explore the tolerability of memantine treatment in FTLD and to monitor for possible effects on behavior, cognition and function. 43 individuals who met clinical criteria for FTLD (21 with frontotemporal dementia [FTD], 13 with semantic dementia [SD] and 9 with progressive nonfluent aphasia [PA]) received 26 weeks of open label treatment with memantine at a target dose of 20 mg daily. Concurrent treatment with acetylcholinesterase inhibitors was prohibited. Cognitive and functional outcome measures included the MMSE, ADAS-cog, CDR-sum of boxes, NPI, Frontal Behavior Inventory (FBI), Executive Interview (EXIT25), Texas Functional Living Scale (TFLS), Geriatric Depression Scale (GDS) and UPDRS-motor scale. Most subjects were able to tolerate the target dose of memantine. A transient improvement was observed on the total NPI score primarily in the FTD group. Variable declines were observed on the ADAS-cog, EXIT25, FBI, NPI, TFLS and UPDRS scores. The FTD and SD groups declined on most of the cognitive and behavioral outcome measures, but remained stable on the UPDRS, whereas the PA group remained relatively stable on the ADAS-cog, NPI and TFLS, but declined on the UPDRS. Memantine was well tolerated in these subjects. Future placebo-controlled trials of memantine in FTLD are warranted and may have greater power to detect behavioral and cognitive effects if focused on the FTD and SD clinical syndromes.
Frontotemporal dementia; semantic dementia; progressive nonfluent aphasia; memantine; open-label treatment study
There are no Food and Drug Administration (FDA)-approved medications indicated for the treatment of frontotemporal dementia (FTD). We sought to determine the most commonly used drugs used to treat behavioral variant FTD (bvFTD) in specialized dementia clinics.
Medication and demographic data from the Alzheimer’s Disease Research Centers of California (ARCC) and a multicenter FTD natural history study (NHS) data set were compared in bvFTD and Alzheimer’s disease (AD), and effects of demographic variables were assessed using logistic regression.
Overall, the percentage of patients taking one or more FDA-approved AD or psychiatric medications was similar in bvFTD and AD; however, after controlling for demographic variables, acetylcholinesterase inhibitor (AChI) use was less common in bvFTD, whereas memantine use remained similar in the 2 groups.
Despite lack of evidence for efficacy, the use of AChIs and memantine is common in bvFTD. Clinical trials should be pursued to determine the optimal therapeutic interventions for bvFTD.
frontotemporal dementia; Alzheimer’s disease; treatment; donepezil; memantine; galantamine; antipsychotic agents
Saw palmetto is commonly used by men for lower urinary tract symptoms. Despite its widespread use, very little is known about the potential toxicity of this dietary supplement.
The Saw palmetto for Treatment of Enlarged Prostates (STEP) study was a randomized clinical trial performed among 225 men with moderate-to-severe symptoms of benign prostatic hyperplasia, comparing a standardized extract of the saw palmetto berry (160mg twice daily) with a placebo over a one-year period. As part of this study, detailed data were collected on serious and non-serious adverse events, sexual functioning, and laboratory tests of blood and urine. Between-group differences were assessed with mixed-effects regression models.
There were no significant differences observed between the saw palmetto and placebo-allocated participants in the risk of suffering at least one serious adverse event (5.4% vs. 9.7%, respectively; p = 0.31) or non-serious symptomatic adverse event (34.8% vs. 30.1%; p = 0.48). There were few significant between-group differences in sexual functioning or for most laboratory analyses, with only small differences observed in changes over time in total bilirubin (p = 0.001), potassium (p = 0.03), and the incidence of glycosuria (0% in the saw palmetto group vs. 3.7% in the placebo group, p = 0.05).
Despite careful assessment, no evidence for serious toxicity of saw palmetto was observed in this clinical trial. Given the sample size and length of this study, however, these data do not rule out potential rare adverse effects associated with the use of saw palmetto.
Subgroups of mild cognitive impairment (MCI) have been proposed, but few studies have investigated the non-amnestic, single-domain subgroup of MCI. The goal of the study was to compare clinical and neuroimaging characteristics of two single domain MCI subgroups: amnestic MCI (aMCI) and dysexecutive MCI (dMCI).
We compared the cognitive, functional, behavioral and brain imaging characteristics of patients with aMCI (n=26), dMCI (n=32) and age- and education-matched controls (n=36) using analysis of variance and chi-squared tests. We used voxel-based morphometry (VBM) to examine group differences in brain MRI atrophy patterns.
Patients with dMCI had significantly lower scores on the majority of executive function tests, increased behavioral symptoms, and left prefrontal cortex atrophy on MRI when compared to controls. In contrast, patients with aMCI had significantly lower scores on tests of memory and a pattern of atrophy including bilateral hippocampi and entorhinal cortex, right inferior parietal cortex, and posterior cingulate gyrus when compared to controls.
Overall, the clinical and neuroimaging findings provide support for two distinct single-domain subgroups of MCI, one involving executive function and the other involving memory. The brain imaging differences suggest that the two MCI subgroups have distinct patterns of brain atrophy.